CN101068823A - Tetrahydropyrane derivatives for use as antidiabetics - Google Patents

Tetrahydropyrane derivatives for use as antidiabetics Download PDF

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CN101068823A
CN101068823A CNA2005800412829A CN200580041282A CN101068823A CN 101068823 A CN101068823 A CN 101068823A CN A2005800412829 A CNA2005800412829 A CN A2005800412829A CN 200580041282 A CN200580041282 A CN 200580041282A CN 101068823 A CN101068823 A CN 101068823A
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salts
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W·梅德尔斯基
C·范阿姆斯特丹
C·伯格
H·格雷纳尔
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Merck Patent GmbH
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Abstract

A minimally invasive intraluminal electrode assembly that includes a cannulated tube and a plurality of wires disposed within the cannulated tube. Each of the plurality of wires has one of a plurality of electrical contacts on a distal end thereof. The distal portion of the plurality of wires assumes a radially constrained configuration within the cannulated tube in a retracted position and a radially extended position outward of the cannulated tube in a deployed position. The electrode assembly further comprises a spring electrode connecting the plurality of electrical contacts to collectively form a substantially circular configuration in a deployed position.

Description

Tetrahydropyran derivatives as antidiabetics
The present invention relates to stereoisomers of compounds of formula I and pharmaceutically acceptable derivatives, solvates, salts and mixtures thereof, including all ratios thereof,
Figure A20058004128200101
wherein:
t represents a six-membered saturated or unsaturated heterocyclic ring having 1 to 3N atoms and/or O atoms,
said heterocycle being ═ O and/or R3Mono-, di-, tri-or tetra-substituted, containing at least one N atom, and the heterocycle is bonded to E via an N atom,
e represents (CH)2)n，
R, R' independently of one another represent OH, F or H, excluding the following four combinations: r ═ F, R ' ═ OH and R ═ OH, R ═ F and R, R ' ═ H and R, R ' ═ OH,
r 'represents OH or F, and R' represents OH or F,
R1is represented by the formula H or COOA,
R2、R2’independently of one another, H, halogen, A, OA or OH,
R3ar, A, OA, OAr, O (CH)2)nAr、NR4R4’Or C (═ O) R5，
R4、R4’Independently of one another, H, A, CHO, C (═ O) A or Ar,
R5h, OA, OAr, O (CH)2)nAr or NR4R4’，
A represents a linear or branched alkyl group having 1 to 10C atoms, wherein one or two CH groups2The radicals may be replaced by O or S atoms and/or-CH ═ CH-groups, and/or further 1 to 7H atoms may be replaced by F atoms,
or cycloalkyl having 3 to 7C atoms,
ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or tri-substituted with: halogen, A, OR6、N(R6)2、NO2、CN、COOR6、CON(R6)2、NR6COA、NR6CON(R6)2、NR6SO2A、COR6、SO2N(R6)2、S(O)pA and/or- [ C (R)6)2]m-COOR6，
R6Represents a group of a compound represented by the formula H or A,
halogen represents F, Cl, Br or I,
m represents a number of 0 or 1,
n represents a number of 1 or 2,
p represents 0, 1 or 2.
The object of the present invention was to find valuable novel compounds which can be used, in particular, for the preparation of medicaments.
It has been found that the compounds of formula I and their salts have very valuable pharmacological properties while being well tolerated. They exhibit the property of inhibiting SGLT 1-and SGLT2- (sodium-dependent glucose co-transporter) and are therefore useful for combating or preventing type I and type II diabetes.
Glucose absorption at the brush border of the small intestine and the renal proximal tubule in the opposite concentration gradient is via the epithelial sodium-dependent glucose cotransporter (SGLT). At least two broad classes of SGLT have been described: SGLT1 (e.g., Lee W.S. et al (1994), high affinity Na)+Glucose co-transporter: re-evaluation of the function and distribution of expression, J.biol.chem., 269, 12032-12039) and SGLT2 (e.g., Mackenzie B et al (1994), SAAT1 is low affinity Na+A/glucose co-transporter, not an amino acid transporter. Biol. chem., 269,22488-22491)。
SGLT1 is thought to be important for glucose absorption in the gut, while SGLT2 may be primarily responsible for the reabsorption of free-filtered glucose in the kidney.
The major change in diabetics is hyperglycemia. This is not only a symptom of the disease, but also a potential causative factor that can lead to a variety of chronic diabetic microvascular and macrovascular complications and impaired insulin secretion and sensitivity functions (Kline R. (1995), diabetic hyperglycemia and microvascular and macrovascular diseases, Diabetes Care 18, 258-. Thus, an important therapeutic goal for diabetic patients is the overall regulation of blood glucose levels within the normal range. According to their stated function, inhibition of SGLT leads to a decrease in glucose absorption and an increase in excretion, and subsequently a decrease in blood glucose levels. Therefore, inhibition of SGLT may be a suitable choice for the treatment of diabetes.
The literature describes many classes of substances with SGLT action. The model for all these structures is the natural product phlorizin. Aromatic glycoside derivatives are known from WO 2004/052902 and WO 2004/052903. WO 280936, WO 280935, JP 2000080041 and EP 850948 describe phenylketosides. WO 0244192, WO 0228872 and WO 0168660 describe glucopyranosyloxybenzylbenzenes. WO 0268440, WO 0268439, WO 0236602 and WO 0116147 describe glucopyranosyloxypyrazoles. WO0174835 and WO 0174834 disclose O-glycoside benzamides. WO 0127128 and US 2002137903 describe C-aryl glycosides. All known structures contain glucose as an important structural element. Furthermore, US 2002/132807 discloses diaryl sulfide compounds for the treatment of inflammatory and immune diseases. EP 0953357 a1 describes in general glucosides as renal drug carriers and WO 95/23780 describes 4-hydroxyphenoxyheterocycloalkyl compounds as skin lightening agents.
The beneficial effects of the compounds of formula I on glucose metabolism are prominent, in particular they lower blood glucose levels and are suitable for the treatment of type I and type II diabetes. The compounds can therefore be used alone or in combination with further blood sugar-lowering active ingredients (antidiabetics).
The compounds of formula I are also suitable for the prophylaxis and treatment of diabetic late damage, for example nephropathy, retinopathy, neuropathy and syndrome X, obesity, myocardial infarction, peripheral vascular occlusive disease, thrombosis, arteriosclerosis, inflammation, immune diseases, autoimmune diseases, such as AIDS, asthma, osteoporosis, cancer, psoriasis, alzheimer's disease, schizophrenia and infectious diseases, preferably in the treatment of type I and type II diabetes, and for the prophylaxis and treatment of diabetic late damage, syndrome X and obesity.
The compounds of formula I are useful as pharmaceutical active ingredients for human and veterinary use, in particular for the treatment and prevention of type I and type II diabetes.
The invention relates to a process for the preparation of compounds of formula I and salts thereof, and compounds of formula I according to claims 1 to 12 and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers, characterized in that compounds of formula II are prepared
Figure A20058004128200131
Wherein,
r, R' independently of one another denote OAc, F or H, excluding the following four combinations: r ═ F, R ═ OAc and R ═ OAc, R ═ F and R, R' ═ H and R, R ═ OAc,
r "represents an OAc or a F,
r * represents an OAc and R * represents an OAc,
R1is expressed as the expression of Ac,
ac represents an acetyl group and a pharmaceutically acceptable salt thereof,
with a compound of the formula III,
Figure A20058004128200132
wherein,
T、E、R2、R2’having the meaning indicated in claim 1,
the acetyl group is then removed and/or the base or acid of the compound of formula I is converted to one of its salts.
The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. The term "solvate of a compound" refers to a substance in which inert solvent molecules are adducted to the compound to form due to their attractive interaction. Solvates are, for example, mono-or dihydrate or alcoholates.
The term "pharmaceutically acceptable derivatives" refers to, for example, salts of the compounds according to the invention and also to so-called prodrug compounds.
The term "prodrug derivative" refers to a compound of formula I which has been modified by, for example, an alkyl or acyl group, a sugar or an oligopeptide and which can be rapidly cleaved in vivo to form the active compounds according to the invention.
Also included are biologically degradable polymer derivatives of the compounds according to the invention, such as, for example, in int.j.pharm.11561-67 (1995).
The invention furthermore relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example mixtures in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. Mixtures of stereoisomeric compounds are particularly preferred.
The compounds according to the invention may also be present in different polymorphic forms, for example amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are within the scope of the invention and are a further aspect of the invention.
For groups that occur more than once, their meanings are independent of each other.
In this context, unless stated otherwise, the radicals or parameters T, E, R, R ', R', R1、R2、R2’The meaning of (a) is as indicated under formula I.
A represents a linear or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2-or 1, 2, 2-trimethylpropyl, very particularly preferably, for example, trifluoromethyl.
A very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.
Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
R preferably represents H.
R' preferably represents OH.
R "preferably represents OH.
R1Preferably H, and furthermore may be COOA, e.g. COOCH3Or COOC2H5。
R2And R2’Preferably represents H.
R3Preferably Ar, A, O (CH)2)nAr、NR4R4’Or C (═ O) R5。
R4、R4’Preferably, independently of one another, H or C (═ O) a.
R5Preferably represents O (CH)2)nAr。
the-COA (acyl) preferably represents acetyl, propionyl, and may additionally represent butyryl, pentanoyl, hexanoyl, or, for example, benzoyl.
Halogen preferably denotes F, Cl or Br and I.
Ar represents, for example, phenyl; o-, m-, or p-methylphenyl; o-, m-, or p-ethylphenyl; o-, m-, or p-propylphenyl; o-, m-, or p-isopropylphenyl; o-, m-, or p-tert-butylphenyl; ortho-, meta-, or para-hydroxyphenyl; o-, m-, or p-nitrophenyl; ortho-, meta-, or para-aminophenyl; o-, m-or p- (N-methylamino) phenyl; o-, m-or p- (N-methyl-aminocarbonyl) phenyl; o-, m-or p-acetamidophenyl; o-, m-, or p-methoxyphenyl; o-, m-, or p-ethoxyphenyl; o-, m-, or p-ethoxycarbonylphenyl; o-, m-or p- (N, N-dimethylamino) phenyl; o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl; o-, m-or p- (N-ethylamino) phenyl; o-, m-or p- (N, N-diethylamino) phenyl; o-, m-or p-fluorophenyl; o-, m-, or p-bromophenyl; o-, m-, or p-chlorophenyl; o-, m-or p- (methylsulfonylamino) phenyl; o-, m-or p- (methylsulfonyl) phenyl, more preferably, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-difluorophenyl; 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dichlorophenyl; 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dibromophenyl; 2, 4-or 2, 5-dinitrophenyl; 2, 5-or 3, 4-dimethoxyphenyl; 3-nitro-4-chlorophenyl; 3-amino-4-chloro-; 2-amino-3-chloro-; 2-amino-4-chloro-; 2-amino-5-chloro-or 2-amino-6-chlorophenyl; 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl; 2, 3-diaminophenyl; 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 2, 4, 6-or 3, 4, 5-trichlorophenyl; 2, 4, 6-trimethoxyphenyl; 2-hydroxy-3, 5-dichlorophenyl; p-iodophenyl; 3, 6-dichloro-4-aminophenyl; 4-fluoro-3-chlorophenyl; 2-fluoro-4-bromophenyl; 2, 5-difluoro-4-bromophenyl; 3-bromo-6-methoxyphenyl; 3-chloro-6-methoxyphenyl; 3-chloro-4-acetylaminophenyl; 3-fluoro-4-methoxyphenyl; 3-amino-6-methylphenyl; 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.
Ar particularly preferably represents, for example, unsubstituted phenyl, furthermore 2-methylsulfonyl-phenyl; 2-, 3-or 4-chlorophenyl; 3, 4-dichlorophenyl; 4-methylphenyl group; 4-bromophenyl; 3-fluoro-4-methoxyphenyl; 4-trifluoromethoxyphenyl; 4-ethoxyphenyl; 2-methoxyphenyl group; 3-cyanophenyl; 4-ethoxycarbonylphenyl; a methoxycarbonylphenyl group; carboxyphenyl or aminocarbonylphenyl. Ar very particularly preferably represents unsubstituted phenyl.
T preferably represents 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or substituted by R3Mono-, di-or tri-substituted.
T particularly preferably represents 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or mono-, di-or trisubstituted by methyl, ethyl, propyl, phenyl, benzyloxycarbonyl, acetylamino, benzyloxy, methoxycarbonyl and/or ethoxycarbonyl.
Substituted 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl.
The compounds of formula I may have one or more chiral centers and may therefore also occur in different stereoisomeric forms. Formula I covers all these forms.
The invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the following formulae from Ia to Ij, which correspond to formula I, wherein the groups not specified have the meanings indicated under formula I, but wherein:
in Ia, T represents 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or substituted by R3Mono-, di-, or tri-substituted;
in Ib, R2、R2’Represents H;
in Ic, R3Ar, A, O (CH)2)nAr、NR4R4’Or C (═ O) R5；
In Id, R4、R4’Independently of one another, represents H or C (═ O) a;
in Ie, R5Represents O (CH)2)nAr；
In If, A represents a linear or branched alkyl group having 1 to 10C atoms, in which 1 to 7H atoms may be replaced by F;
in Ig, Ar represents unsubstituted or substituted halogen, A, OA, NH2、NO2CN, COOA and/or CONH2Mono-, di-, or tri-substituted phenyl;
in Ih, Ar represents phenyl;
in Ii, R represents H,
r 'represents an OH group, and R' represents an OH group,
r' represents OH;
in Ij, T represents 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or substituted by R3Mono-, di-, or tri-substituted;
e represents (CH)2)n，
R represents a hydrogen atom or a hydrogen atom,
r 'represents an OH group, and R' represents an OH group,
r 'represents an OH group, and R' represents an OH group,
R1the expression "H" is used to indicate the formula,
R2、R2’the expression "H" is used to indicate the formula,
R3ar, A, O (CH)2)nAr、NR4R4’Or C (═ O) R5，
R4、R4’Independently of one another, H or C (═ O) A,
R5represents O (CH)2)nAr，
A represents a linear or branched alkyl group having 1 to 10C atoms, in which 1 to 7H atoms may be replaced by F,
ar represents a phenyl group, and Ar represents a phenyl group,
halogen represents F, Cl, Br or I,
n represents 1 or 2;
and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios.
The compounds of the formula I and the starting materials for their preparation can also be prepared by Methods known per se, such as are described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemistry [ Methods of Organic Chemistry ], Georg-Thieme-Verlag, Stuttgart), to be precise by carrying out the reaction under reaction conditions known and suitable for the reaction in question. Variants known per se but not described in more detail here can also be used.
If desired, the starting materials can also be formed in situ, so that they can be converted further into the compounds of the formula I immediately without isolation from the reaction mixture.
The starting compounds of the formulae II and III are well known. If new, they can be prepared by methods known per se.
The compound of formula I is preferably obtained by reacting a compound of formula II with a compound of formula III.
The reaction is generally carried out in an inert solvent in the presence of an acid coupling agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, or other weak alkali metal or alkaline earth metal acid salts, preferably potassium, sodium, calcium or cesium salts, an organic base such as triethylamine, dimethylaniline, pyridine or quinoline, or the addition of an excess of the phenol component of formula II or of the alkylated derivative of formula III may also be advantageous. Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about 0 ℃ to 150 ℃ and usually from 20 ℃ to 130 ℃.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, isopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.
The reaction is preferably carried out in the presence of a phase transfer catalyst, for example, tributylbenzylammonium chloride.
Hydroxy protecting groups, such as acetyl, can be removed by methods known to those skilled in the art.
Pharmaceutically acceptable salts and other forms
Said compounds of formula I may be used in their final non-salt form. In another aspect, the invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be prepared from various inorganic and organic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared in large part by conventional methods. If the compound of formula I contains a carboxyl group, a suitable salt thereof may be formed by reacting said compound with a suitable base to form the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methyl glutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating such compounds with pharmaceutically acceptable organic and inorganic acids (such as hydrogen halides, for example, hydrogen chloride, hydrogen bromide and hydrogen iodide), other mineral acids and their corresponding salts (such as sulfates, nitrates or phosphates, and the like) and alkyl-and monoaryl sulfonates (such as ethanesulfonates, toluenesulfonates and benzenesulfonates), and other organic acids and their corresponding salts (such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates, and the like). Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include, without limitation, the following salts: acetate, adipate, alginate, arginate (arginate), aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (galactarate) (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, dihydrocarb, Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzenesulfonate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate (palmoate), pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate.
In addition, base salts of compounds of formula I include, without limitation, aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganous (II), potassium, sodium and zinc salts. Among the above salts, ammonium salts are preferred; alkali metal salts such as sodium and potassium salts; and alkaline earth metal salts such as calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable non-toxic organic bases include, without limitation, salts of primary, secondary and tertiary amines, salts of substituted amines (including naturally occurring substituted amines), salts of cyclic amines, and salts of basic ion exchange resins, e.g., with arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, and mixtures thereof, Triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (aminotributanol).
May be used as (C)1-C4) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; two (C)1-C4) Alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates; (C)10-C18) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)1-C4) Reagents such as alkyl halides, e.g., benzyl chloride and phenethyl bromide, quaternize compounds of formula I that contain basic nitrogen-containing groups. Both water-soluble and oil-soluble compounds of formula I can be prepared using such salts.
Preferred such pharmaceutically acceptable salts include, without limitation, acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and aminotrimethalin salts.
The acid addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting its salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, the salts are comparable to their respective free base forms.
As mentioned, pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
Base addition salts of the acidic compounds of formula I are prepared by contacting the free acid form thereof with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are comparable to their respective free acid forms.
If the compounds of formula I contain more than one group which form pharmaceutically acceptable salts of this type, the invention also includes complex salts. Typical complex salt forms include, for example, without limitation, ditartrate, diacetate, difumarate, diglucomethane, diphosphate, disodium salt, and trihydrochloride.
In the above context, the term "pharmaceutically acceptable salt" in this context refers to an active ingredient comprising a compound of formula I in one of its salt forms, in particular in the form of a salt which confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient used before. The pharmaceutically acceptable salts of the active ingredients may also confer for the first time the desired pharmacokinetic properties not previously possessed by the active ingredients and may even have a positive effect on the pharmacodynamics of the active ingredients with respect to their efficacy in vivo.
The compounds of the formula I according to the invention can, owing to their molecular structure, be chiral and can therefore occur in different enantiomeric forms. They may thus exist in racemic or optically active form.
Since the pharmaceutical activity of racemates or stereoisomers of the compounds according to the present invention may differ, it may be desirable to use enantiomers thereof. In these cases, the end products or even intermediates can be isolated by chemical or physical methods known to the person skilled in the art or even synthetically prepared into the enantiomeric compounds.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the R or S form of suitable N-protected amino acids such as N-benzoylproline or N-phenylsulphonylproline, or various optically active camphorsulphonic acids. It is also advantageous to carry out the chromatographic separation of the enantiomers with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chiral derivatives of methacrylic acid polymers fixed on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile, for example in the ratio 82: 15: 3.
The invention also relates to the use of said compounds and/or their physiologically acceptable salts for the production of medicaments (pharmaceutical compositions), in particular by non-chemical methods. It may be converted into suitable dosage forms herein with at least one solid, liquid and/or semi-liquid excipient or adjuvant, optionally in combination with one or more additional active ingredients.
The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.
These compositions are useful as human or veterinary medicaments.
The pharmaceutical preparations may be administered in dosage unit form containing a predetermined number of active ingredients per dosage unit. Depending on the disease state to be treated, the method of administration and the age, weight and condition of the patient, such units may contain, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, or these pharmaceutical preparations may be administered in the form of dosage units containing a predetermined number of active ingredients per dosage unit. Preferred dosage unit formulations are those containing the above-described daily dose or partial dose, or a fraction thereof, of the active ingredient. Furthermore, pharmaceutical preparations of this type can be prepared by methods generally known in the art of pharmacy.
These pharmaceutical formulations may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by all methods known in the art of pharmacy, for example by bringing into association the active ingredient with excipients or auxiliaries.
Pharmaceutical formulations adapted for oral administration may be administered in the form of discrete units, such as capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam-like foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic pharmaceutically acceptable inert excipient such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine powder size and mixing it with a pharmaceutically acceptable excipient, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol, which is comminuted in the same manner. Flavouring, preservative, dispersing agents and dyes may likewise be present.
Capsules can be prepared by preparing a powder mixture as described above and filling it into shaped gelatin shells. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as, for example, agar-agar, calcium carbonate or sodium carbonate may also be added thereto to improve the availability of the drug after the capsule is taken.
In addition, if desired, suitable binders, lubricants and disintegrants and also dyes can likewise be admixed with the mixture.
Suitable binders include starch, gelatin, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets may be prepared, for example, by preparing a powder mixture, granulating or dry-compressing the powder mixture, adding a lubricant and disintegrant thereto, and compressing the entire mixture into a tablet. Powder mixtures may be prepared by mixing the compounds, which are comminuted in a suitable manner to a powder, with the above-mentioned diluents or bases and optionally binders, such as, for example, carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders, such as, for example, paraffin, absorption promoters, such as, for example, quaternary salts, and/or absorbents, such as, for example, bentonite, kaolin and dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder, such as, for example, syrup, starch paste, gum arabic or a solution of cellulose or polymer material and compressing it through a sieve. As an alternative to granulation, the powder mixture may be processed with a tablet press to give non-uniformly shaped pieces which are broken up to form granules. These granules may be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent them from sticking to the dies of the tablet press. The lubricated mixture may then be compressed into tablets. It is also possible to combine the compounds of the invention with free-flowing inert excipients and then compress them directly into tablets without a granulation or dry compression step. There may be a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.
Oral liquids, such as, for example, solutions, syrups and elixirs, can be prepared in dosage unit form so that a given quantity can contain a predetermined quantity of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs can be prepared with non-toxic alcohol bases. Suspensions may be prepared by dispersing the compound in a non-toxic base. Solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring agents, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, and the like, may likewise be added.
Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulation may also be prepared in a form in which the release is extended or retarded, for example by coating or embedding the particulate material in a polymer, wax or the like.
The compounds of formula I and salts, solvates and physiologically functional derivatives thereof may also be administered in the form of liposomal delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as, for example, cholesterol, stearylamine, or stearylcholine.
The compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof and other active ingredients may also be delivered using a monoclonal antibody as a separate carrier by coupling the compound to the antibody. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylaminophenol, polyhydroxyethylaspartamido (asparatamido) phenol, or polyethylene oxide polylysine (substituted with palmitoyl). The compounds may also be coupled with a class of biodegradable polymers suitable for obtaining controlled release of a drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or araliphatic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be administered as a stand-alone plaster in intimate contact with the epidermis of the recipient for an extended period of time. Thus, for example, the active ingredient may be delivered from the plaster by iontophoresis (as described in the general term of Pharmaceutical Research, 3(6), 318 (1986)).
Pharmaceutical compounds suitable for topical administration may be prepared in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissues, such as the mouth and skin, the formulation is preferably applied in the form of a topical ointment or cream. In the case of ointment formulations, the active ingredient may be employed with a paraffinic or water-miscible cream base. Alternatively, the active ingredient may be prepared as a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.
Pharmaceutical preparations suitable for topical application in the mouth include lozenges, pastilles and mouthwashes.
Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.
Pharmaceutical preparations suitable for nasal administration in which the carrier substance is a solid are a solid comprising a coarse powder with a particle size of, for example, 20-500 microns, which is administered in the form of an olfactory preparation, i.e. by rapid inhalation through the nasal passage from a container containing the powder which is lifted up to the vicinity of the nose. Suitable formulations for administration in the form of nasal sprays or nasal drops with liquid as carrier material comprise a solution of the active ingredient in water or oil.
Pharmaceutical formulations adapted for administration by inhalation comprise a fine particle dust or mist which may be generated by various types of pressurized dispensers, nebulizers or inhalers with an aerosol.
Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations suitable for parenteral administration include aqueous or non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending media and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
Injectable solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.
It goes without saying that, in addition to the components specifically mentioned above, for a particular type of formulation, the formulation may also comprise other substances customary in the art; thus, for example, formulations suitable for oral administration may contain flavouring agents.
The therapeutically effective amount of the compound of formula I and other active ingredients will depend on a number of factors including, for example, the age and weight of the animal, the precise disease state to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the physician or veterinarian performing the treatment. However, an effective amount of the compound is usually 0.1 to 100mg/kg body weight of the recipient (mammal) per day, and particularly typically 1 to 10mg/kg body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, where these amounts may be administered in a single dose per day or may be administered in a series of partial doses (such as, for example, two, three, four, five or six) per day such that the total daily dose is the same. The effective amount of the salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound per se.
The invention further relates to the use of a compound of formula I in combination with at least one other pharmaceutically active ingredient, preferably for the treatment of type 1 and type 2 diabetes, in particular for lowering blood glucose.
Other suitable active ingredients for the combination product are as follows:
all antidiabetic drugs mentioned in Rote Liste [ Red List ]2001, chapter 12. They can be combined with the compounds of the formula I according to the invention, in particular for synergistic effects. The active ingredient combination can be administered by separate administration of the several active ingredients to the patient or in the form of a combination product in which the several active ingredients are present in a single pharmaceutical preparation. Most of the active ingredients listed below have been disclosed in USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2001.
Antidiabetic agents include insulin and insulin derivatives, e.g. Lantus®(see www.lantus.com) or HMR 1964, rapid acting insulin (see US patent 6,221,633), GLP-1 derivatives such as those disclosed by Novo Nordisk A/S in WO98/08871, and orally active hypoglycemic active ingredients.
Orally active hypoglycemic active ingredients preferably include sulfonylureas, biguanides, meglitinides (meglitinides), oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers, such as those disclosed by Novo Nordisk a/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism, such as anti-hyperlipidemic and antilipemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists, and active ingredients which act on the ATP-dependent potassium channels of the beta cells.
In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin or rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, for example ezetimibe (ezetimibe), tiquinane or pamabrin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR γ agonist, for example rosiglitazone, pioglitazone, JTT-501 or GI 262570.
In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, for example GW 9578 or GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed α/γ agonist, for example GW 1536, AVE 8042, AVE 8134, AVE 0847, AVE 0897, or as disclosed in WO 00/64888, WO 00/64876, WO 03/20269.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, for example fenofibrate, clofibrate or bezafibrate.
In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, for example, Inteptapede (impiriade), BMS-201038 or R-103757. In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor (see, e.g., U.S. patent 6,245,744 or 6,221,897), such as HMR 1741.
In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, e.g., JTT-705.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, for example cholestyramine or colesevelam (colesevelam).
In one embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor inducing agent (see U.S. patent 6,342,512), e.g., HMR1171, HMR 1586.
In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, for example avasimibe (avasimibe).
In one embodiment of the invention, the compounds of the formula I are applied in combination with antioxidants, for example OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, for example NO-1886.
In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor, e.g., SB-204990.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, for example BMS-188494. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist, for example CI-1027 or nicotinic acid. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula I are administered in combination with sulfonylureas, for example tolbutamide, glyburide, glipizide or glimepiride.
In one embodiment, the compound of formula I is administered in combination with a biguanide, for example metformin.
In one embodiment, the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.
In one embodiment, the compounds of formula I are administered in combination with a thiazolidinedione, such as, for example, compounds disclosed in WO97/41097 by troglitazone, ciglitazone, pioglitazone, rosiglitazone or the Reddy's doctor research foundation, especially 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl ] methyl ] -2, 4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of formula I are administered in combination with more than one of the above compounds, for example in combination with sulfonylureas and metformin, sulfonylureas and acarbose, repaglinide and metformin, insulin and sulfonylureas, insulin and metformin, insulin and troglitazone, insulin and lovastatin, and the like.
In another embodiment, the compound of formula I is administered in combination with: CART modulators (see, "cocaine-amphetamine regulated transcription affects energy metabolism, anxiety and gastric emptying in mice," Asakawa, A, et al, M.: Hormone and Metabolic Research (2001), 33(9), 554-); NPY antagonists, e.g. naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl]Cyclohexylmethyl } amide, hydrochloride (CGP 71683A)) ); MC4 agonists (e.g., 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3 a-benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydropyrazolo [4, 3-c ]]Pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl]Amides (WO 01/91752)); feeding factor (orexin) antagonists (e.g. 1- (2-methylbenzoxazol-6-yl) -3- [1, 5]Naphthyridin-4-ylurea), hydrochloride (SB-334867-a)); h3Agonist (3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c)]Pyridin-5-yl) propan-1-one oxalate (WO 00/63208)); a TNF agonist; CRF antagonists (e.g. [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl)]Dipropylamine (WO 00/66585)); CRF BP antagonists (e.g., ulodine); a Yololidine agonist; beta 3-agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino]Ethanol, hydrochloride salt (WO 01/83451)); MSH (melanocyte stimulating hormone) agonists; CCK-A agonists (e.g. {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl]-5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate salt (WO 99/15525)); 5-hydroxytryptamine reuptake inhibitors (e.g., dexfenfluramine); mixed 5-hydroxytryptamine and norepinephrine compounds (e.g., WO 00/71549); 5HT agonists, such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111); bombesin agonists; galanin antagonists; growth hormone (e.g., human growth hormone); a growth hormone releasing compound (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)); TRH agonists (see, e.g., EP 0462884); uncoupling protein 2-or 3-modulators; leptin agonists (see, e.g., Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia, leptin agonists as a potential route for the treatment of obesity. Drugs of the Future (2001), 26(9), 873-); DA agonists (bromocriptine, Doprexin); lipase/amylase inhibitors (e.g., WO 00/40569); PPAR modulators (e.g. WO 00/78312); RXR modulators or TR-beta agonists.
In one embodiment of the invention, the other active ingredient is leptin; see, e.g., "therapeutic application prospects for leptin" Salvador, Javier; gomez Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.
In one embodiment, the additional active ingredient is dextroamphetamine or amphetamine.
In one embodiment, the additional active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the additional active ingredient is sibutramine.
In one embodiment, the additional active ingredient is orlistat.
In one embodiment, the additional active ingredient is mazindol or phentermine.
In one embodiment, the compounds of formula I are administered in combination with a dietary fibrous substance, preferably an insoluble dietary fibrous substance (see, e.g., Carob/Caromax)®(Zunft H J; et al, carob bean milk products for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (9-10 months 2001), 18(5), 230-6), Caromax®Is Nutrinova, Nutrition Specialties&FoodIngredients GmbH, Industrie park Hochst, 65926 Frankfurt/Main company, carob-containing products)). And Caromax®May be effected in a single composition, or by separate administration of the compound of formula I and Caromax®To be implemented. Caromax®It can also be administered in the form of a food product, for example in bread or a milkbreakfast bar.
It is to be understood that each suitable combination of a compound of the invention with one or more of the above compounds (and optionally one or more other pharmacologically active substances) is within the scope of the present invention.
Figure A20058004128200311
The invention also relates to a device (kit) consisting of the following individual packages
(a) An effective amount of a compound of formula I and/or pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof (including mixtures thereof in all ratios), and
(b) an effective amount of an additional pharmaceutically active ingredient.
The device comprises a suitable container such as a box or carton, individual bottles, bags or ampoules. The device may for example comprise separate ampoules each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further pharmaceutically active ingredient, which may be in dissolved or freeze-dried form.
The SGLT inhibitory properties of the compounds can be tested by methods of SGLT1 and SGLT2 expressing BHK cells. Production and testing of cells can be performed as follows.
Construction and expression of SGLT1 in BHK cells
To construct an expression vector for SGLT1 (KL225), the SLC5a1 gene (homologous to NM — 000343) was amplified from a cDNA library using standard PCR techniques and cloned into pcdna3.1 expression vector (Invitrogen) containing neomycin as a selectable marker at the Nhel/Xhol site. In this vector, transcription uses human cytomegalovirus as an enhancer/promoter.
The final vector KL225 was introduced into the cells together with another vector containing the dihydrofolate reductase gene as a selection marker. In accordance with Graham f.l. and van der Ebb, A.J. (1973), Virology 52: 456 Using calcium phosphate transfection, pair 107BHK21 cells cultured in DMEM medium (GIBCO/BRL) supplemented with 10% Fetal Calf Serum (FCS) and 20mM glutamine were transfected into BHK21 cells using 5-20. mu.g of uncut plasmid. The stable transfectant is selected from the group consisting of G418(GIBCO/BRL) at 1mg/ml and a final concentration of 20-50A culture medium of 00nM methotrexate in which only cells expressing the neomycin gene and overexpressing the dhfr gene are able to grow. After 2-3 weeks of growth, cells were cloned (0.5 cells/well) and the cloned cells were investigated for SGLT expression using a radioactive uptake assay.
Construction and expression of SGLT2 in BHK cells
To construct the SGLT2 expression vector (KL224), the SLC5A2 gene (homologous to NM-003041) was amplified from a cDNA library using standard PCR techniques and cloned into the PCI-neo expression vector (Promega) containing neomycin as a selectable marker at the Nhel/Xhol site. In this vector, human cytomegalovirus is used for transcription as an enhancer/promoter and SV40 polyadenylation signal.
The final vector KL224 was introduced into the cells together with another vector containing the dihydrofolate reductase gene as a selection marker. According to Graham f.l. and van der Ebb, A.J. (1973), Virology) 52: 456 Using calcium phosphate transfection, pair 107BHK21 cells cultured in DMEM medium (GIBCO/BRL) supplemented with 10% Fetal Calf Serum (FCS) and 20mM glutamine were transfected into BHK21 cells using 5-20. mu.g of uncut plasmid. The stable transfectants were selected from the group consisting of medium containing 1mg/ml of G418(GIBCO/BRL) and methotrexate at a final concentration of 20-5000nM, in which only cells expressing the neomycin gene and overexpressing the dhfr gene were able to grow. After 2-3 weeks of growth, cells were cloned (0.5 cells/well) and the cloned cells were investigated for SGLT expression using a radioactive uptake assay.
Method for determining SGLT1/2 activity
In principle, the method comprises the following steps of,14the uptake of C-. alpha. -methyl-D-glucopyranoside (AMG) in, for example, oocytes of toads injected with the corresponding cRNA has been described in the literature (e.g., Wen-Sen Lee et al (1994), J.biol. chem.269, 12032-12039; Guofeng You et al (1995), J.biol. chem.270, 29365-29371).
A 96-well plate cell-based assay was established and adapted to the needs of HTS:
BHK cells (transfected SLGT1 or SLGT2) were seeded into 96-well microtiter plates (culture plates, Perkin Elmer). After at least 24h, the medium is removed and buffered (140mM NaCl, 2mM KCl, 1mM CaCl)2，1mM MgCl210mM HEPES, 5mM Tris, adjusted to pH7.4 with 1 MKOH) was washed. After addition of 40. mu.l buffer, 50. mu.l AMG (50. mu.M for SGLT1 and 2mM for SGLT2) with and without compound, the cells were incubated in a total volume of 100. mu.l at 37 ℃ for 90 min. The supernatant was aspirated off and discarded. Cells were washed and dissolved by adding 50. mu.l of water. After 10min at room temperature, 200. mu.l Microscint 40(PerkinElmer) was added. Radioactivity counts were performed in a Topcount microplate scintillation counter (Perkin Elmer). In sodium-free buffer (266mM sucrose, 2mM KCl, 1mM CaCl)2、1mM MgCl210mM HEPES, 5mM Tris, adjusted to pH7.4 with 1M KOH) was assayed for non-specific uptake.
Above and below, all temperatures are in degrees Celsius. In the following examples, "conventional processing" means: if necessary, water is added, the pH is adjusted, if necessary, to a value between 2 and 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate and dichloromethane, the phases are separated, the organic phase is dried with sodium sulfate and evaporated, and the product is chromatographed on silica gel and/or crystallized. Rf value on silica gel, eluent: ethyl acetate/methanol 9: 1.
Mass Spectrum (MS): EI (Electron impact ionization) M+
FAB (fast atom bombardment) (M + H)+
ESI (electrospray ionization) (M + H)+(unless otherwise stated)
Example 1
The preparation of 4-ethyl-1- [2- ((2S, 3R, 4S, 5S, 6R) -3, 4, 5-trihydroxy-6-hydroxymethyltetrahydropyran-2-yloxy) -benzyl ] -1H-pyridin-2-one ("1") is carried out analogously to the following scheme:
Figure A20058004128200341
1. 4.26g (0.038mol) of potassium tert-butoxide are added to 4.25g (0.035mol) of ethylpyridone dissolved in 50ml of DMF1a(prepared in a similar manner to the methyl compound described in chem. be. 1924, 57, 794) the mixture was stirred at room temperature for 30 min. Then 5.95g (0.038mol) of 2-methoxybenzyl chloride are slowly added dropwise2aThe mixture was stirred at room temperature for 18 h. The mixture was then worked up conventionally to give 7.5g (89%) of methoxybenzylpyridone3aThe crude product of (1); MS-EI (M)+)＝243。
2. 7.5g (0.031mol) of methoxybenzylpyridinone3aDissolved in 150ml of DCM, the mixture was cooled to 5 ℃ and 14.63ml (0.154mol) of boron tribromide dissolved in 50ml of DCM was added dropwise with stirring, after which the mixture was stirred at room temperature for 18 h. The mixture was then worked up conventionally to give 6.73g (95%) of hydroxybenzylpyridone as an oil4a；MS-EI(M+)＝229。
3. 5.0g (0.022mol) of hydroxybenzylpyridone in 250ml of chloroform4a18.1g (0.044mol) of D- (+) -alpha-acetylbromoglucose5a1.37g (4.4mmol) of benzyltributylammonium chloride and 15.2g (0.1mol) of potassium carbonate are stirred at room temperature under nitrogen for 2 days. The mixture was then worked up conventionally to give 2.48g (20%) of the tetraacetate6a；MS-EI(M+)＝559。
4. 1.0g (1.8mmol) of tetraacetate6aDissolved in 30ml of methanol, the mixture was cooled to 5 ℃ and purged with ammonia for 30 min. The mixture was then stirred at room temperature for a further 18 h. The mixture was then worked up conventionally to give 505mg (72%) of "1", m.p.174 ℃, MS-EI (M)+)＝391。
The following compounds are similarly available.
Figure A20058004128200351
Figure A20058004128200361
Figure A20058004128200371
Figure A20058004128200381
The following examples relate to pharmaceutical compositions:
example A: injection vial
A solution of 100g of the active ingredient of the formula I and 5g of disodium hydrogenphosphate in 3l of bidistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, filter-sterilized, transferred into injection vials, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.
Example B: suppository
A mixture of 20g of active ingredient of the formula I with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20mg of active ingredient.
Example C: solutions of
In 940ml of water, 1g of active ingredient of the formula I, 9.38g of NaH2PO4·2H2O、28.48g Na2HPO4·12H2O and 0.1g benzalkonium chloride to prepare a solution. The pH was adjusted to 6.8, the volume of the solution was adjusted to 1l and it was radiation sterilized. This solution can be used in the form of eye drops.
Example D: ointment
500mg of the active ingredient of the formula I are mixed with 99.5g of vaseline under sterile conditions.
Example E: tablet formulation
A mixture of 1kg of active ingredient of the formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10mg of active ingredient.
Example F: coated tablet
Tablets are compressed similarly to example E and subsequently coated in a conventional manner with coating materials such as sucrose, potato starch, talc, tragacanth and dyes.
Example G: capsule
2kg of active ingredient of the formula I are introduced into hard gelatin capsules in the customary manner such that each capsule contains 20mg of active ingredient.
Example H: ampoule agent
A solution of 1kg of the active ingredient of the formula I in 60l of bidistilled water is filtered sterile, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (20)

1. Stereoisomers of compounds of formula I and pharmaceutically acceptable derivatives, solvates, salts and mixtures thereof, including all ratios thereof,
Figure A2005800412820002C1
wherein:
t represents a six-membered saturated or unsaturated heterocyclic ring having 1 to 3N atoms and/or O atoms,
said heterocycle being ═ O and/or R3Mono-, di-, or tri-substitutedSubstituted or tetrasubstituted, containing at least one N atom, and the heterocycle is bonded to E via the N atom,
e represents (CH)2)n，
R, R' independently of one another represent OH, F or H, excluding the following four combinations: r ═ F, R ' ═ OH and R ═ OH, R ═ F and R, R ' ═ H and R, R ' ═ OH,
r 'represents OH or F, and R' represents OH or F,
R1is represented by the formula H or COOA,
R2、R2’independently of one another, H, halogen, A, OA or OH,
R3ar, A, OA, OAr, O (CH)2)nAr、NR4R4’Or C (═ O) R5，
R4、R4’Independently of one another, H, A, CHO, C (═ O) A or Ar,
R5h, OA, OAr, O (CH)2)nAr or NR4R4’，
A represents a linear or branched alkyl group having 1 to 10C atoms, wherein one or two CH groups2The radicals may be replaced by O or S atoms and/or-CH ═ CH-groups, and/or further 1 to 7H atoms may be replaced by F atoms,
or cycloalkyl having 3 to 7C atoms,
ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or tri-substituted with: halogen, A, OR6、N(R6)2、NO2、CN、COOR6、CON(R6)2、NR6COA、NR6CON(R6)2、NR6SO2A、COR6、SO2N(R6)2、S(O)pA and/or- [ C (R)6)2]m-COOR6，
R6Represents a group of a compound represented by the formula H or A,
halogen represents F, Cl, Br or I,
m represents a number of 0 or 1,
n represents a number of 1 or 2,
p represents 0, 1 or 2.
2. A compound according to claim 1 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
T represents 2-oxopyridin-1-yl, 3-oxopyridazin-2-yl, 2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or substituted by R3Mono-, di-or tri-substituted.
3. A compound according to claim 1 or 2 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
R2、R2’Represents H.
4. A compound according to one or more of claims 1 to 3 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
R3Ar, A, O (CH)2)nAr、NR4R4’Or C (═ O) R5。
5. The compounds according to one or more of claims 1 to 4 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
R4、R4’Independently of one another, represents H or C (═ O) a.
6. The compounds according to one or more of claims 1 to 5 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
R5Is represented by the following formula (I)CH2)nAr。
7. The compounds according to one or more of claims 1 to 6 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
A represents a straight-chain or branched alkyl group having 1 to 10C atoms, wherein 1 to 7H atoms may be replaced by F.
8. A compound according to one or more of claims 1 to 7 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
Ar represents unsubstituted or substituted halogen, A, OA, NH2、NO2CN, COOA and/or CONH2Mono-, di-or tri-substituted phenyl.
9. A compound according to claims 1-8 and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
Ar represents phenyl.
10. A compound according to one or more of claims 1 to 9 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
R represents a hydrogen atom or a hydrogen atom,
r 'represents an OH group, and R' represents an OH group,
r' represents OH.
11. A compound according to one or more of claims 1 to 10 and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein
T represents a 2-oxopyridin-1-yl group, a 3-oxopyridazin-2-yl group, a,2, 3-dioxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperidin-1-yl, 2-oxotetrahydropyrimidin-1-yl, 2-oxopyrimidin-1-yl, 4-oxopyridin-1-yl or 3-oxomorpholin-4-yl, each of which is unsubstituted or substituted by R3Mono-, di-or tri-substituted,
e represents (CH)2)n，
R represents a hydrogen atom or a hydrogen atom,
r 'represents an OH group, and R' represents an OH group,
r 'represents an OH group, and R' represents an OH group,
R1the expression "H" is used to indicate the formula,
R2、R2’the expression "H" is used to indicate the formula,
R3ar, A, O (CH)2)nAr、NR4R4’Or C (═ O) R5，
R4、R4’Independently of one another, H or C (═ O) A,
R5represents O (CH)2)nAr，
A represents a linear or branched alkyl group having 1 to 10C atoms, in which 1 to 7H atoms may be replaced by F,
ar represents a phenyl group, and Ar represents a phenyl group,
halogen represents F, Cl, Br or I,
n represents 1 or 2.
12. A stereoisomer according to claim 1, of a compound selected from the group consisting of the following and pharmaceutically acceptable derivatives, solvates, salts and mixtures thereof, including all ratios thereof
Figure A2005800412820005C1
Figure A2005800412820006C1
Figure A2005800412820008C1
。
13. Process for the preparation of compounds of formula I according to claims 1 to 12 and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, characterized in that compounds of formula II are used
Figure A2005800412820008C2
Wherein,
r, R' independently of one another denote OAc, F or H, excluding the following four combinations: r ═ F, R ═ OAc and R ═ OAc, R ═ F and R, R' ═ H and R, R ═ OAc,
r "represents an OAc or a F,
r * represents an OAc and R * represents an OAc,
R1is expressed as the expression of Ac,
ac represents an acetyl group and a pharmaceutically acceptable salt thereof,
with a compound of the formula III,
Figure A2005800412820009C1
wherein,
T、E、R2、R2’having the meaning indicated in claim 1,
the acetyl group is then removed and/or the base or acid of formula I is converted to a salt thereof.
14. Medicament comprising at least one compound of the formula I according to one or more of claims 1 to 12 and/or its pharmaceutically acceptable derivatives, solvates, salts and stereoisomers including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.
15. Medicament comprising at least one compound of the formula I according to one or more of claims 1 to 12 and/or the stereoisomers thereof, pharmaceutically acceptable derivatives, solvates and mixtures thereof including all ratios, and comprising at least one further pharmaceutically active ingredient.
16. Use of a compound according to one or more of claims 1 to 12 and/or physiologically acceptable salts, salts and solvates thereof for the preparation of a medicament for the treatment of type 1 and type 2 diabetes.
17. Use of a compound according to one or more of claims 1 to 12 and/or physiologically acceptable salts, salts and solvates thereof for the preparation of a medicament for lowering blood glucose.
18. Use of a compound according to one or more of claims 1 to 12 and/or physiologically acceptable salts, salts and solvates thereof and other pharmaceutically active ingredients for the preparation of a medicament for the treatment of type 1 and type 2 diabetes.
19. Device (kit) consisting of the following individual packages
(a) An effective amount of a compound of the formula I according to one or more of claims 1 to 12 and/or pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, and
(b) an effective amount of an additional pharmaceutically active ingredient.
20. Use of a compound according to one or more of claims 1 to 12 and/or physiologically acceptable salts, salts and solvates thereof and other pharmaceutically active ingredients for the preparation of a medicament for lowering blood glucose.
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